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Jab1 is a target of EGFR signaling in ERalpha-negative breast cancer.

Wang J, Barnes RO, West NR, Olson M, Chu JE, Watson PH - Breast Cancer Res. (2008)

Bottom Line: EGF treatment of cell lines resulted in increased Jab1 nuclear expression.This effect was inhibited by the ERK pathway inhibitor, PD98059.EGF treatment was also associated with colocalization of pERK (phosphorylated ERK) and Jab1 as well as regulation of the Jab1 downstream target gene, p27.

View Article: PubMed Central - HTML - PubMed

Affiliation: Deeley Research Center, BC Cancer Agency, Vancouver Island Center, Victoria, BC, Canada.

ABSTRACT

Introduction: c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional signaling protein that previously has been shown to be a master regulator of a poor prognostic gene signature in invasive breast cancer and to mediate the action of S100A7. Since epidermal growth factor receptor (EGFR), like S100A7, is often expressed in estrogen receptor-alpha-negative (ERalpha-) breast cancer, we set out to investigate the role of Jab1 in mediating EGFR signaling, another facet of the ERalpha- phenotype.

Methods: MDA-MB-231 and MDA-MB-468 ERalpha-/EGFR+ cell lines were assessed for localization of Jab1 and levels of downstream genes by immunofluorescence and nuclear protein extract assay following treatment with epidermal growth factor (EGF) and extracellular signal-regulated kinase (ERK) pathway inhibitor. A cohort of 424 human breast tumors was also assessed by immunohistochemistry.

Results: EGF treatment of cell lines resulted in increased Jab1 nuclear expression. This effect was inhibited by the ERK pathway inhibitor, PD98059. EGF treatment was also associated with colocalization of pERK (phosphorylated ERK) and Jab1 as well as regulation of the Jab1 downstream target gene, p27. When Jab1 activity was knocked down, p27 levels were restored to pre-EGF treatment level. Analysis of EGFR and Jab1 expression in a cohort of invasive breast tumors by tissue microarray and immunohistochemistry confirmed a relationship between EGFR and increased nuclear Jab1 within the ERalpha- subset (n = 154, P = 0.019). The same association was also confirmed for S100A7 and Jab1 (P = 0.036), and high Jab1 nuclear expression was most frequent in tumors that were positive for both EGFR and S100A7 (P = 0.004).

Conclusion: Jab1 is a target of EGFR signaling in ERalpha- cell lines and breast tumors and therefore may be a common central factor and potential therapeutic target for important cell signaling pathways in ERalpha- breast cancer.

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Jab1 nuclear expression correlates with increased EGFR and S100A7 in breast tumors. EGFR, S100A7, and Jab1 were detected by immunohistochemistry in breast tumors represented within a tissue microarray. Representative staining is shown for all three markers and in three separate tumors. Tumor #188 (top row) shows high nuclear Jab1 expression associated with high EGFR and S100A7 expression. Tumor #226 (middle row) shows intermediate nuclear and cytoplasmic Jab1 expression associated with moderate EGFR and absence of S100A7 expression. Tumor #230 (bottom row) shows low nuclear but high cytoplasmic Jab1 expression associated with the absence of EGFR or S100A7 expression. EGFR, epidermal growth factor receptor; Jab1, c-Jun activation domain-binding protein-1.
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Figure 5: Jab1 nuclear expression correlates with increased EGFR and S100A7 in breast tumors. EGFR, S100A7, and Jab1 were detected by immunohistochemistry in breast tumors represented within a tissue microarray. Representative staining is shown for all three markers and in three separate tumors. Tumor #188 (top row) shows high nuclear Jab1 expression associated with high EGFR and S100A7 expression. Tumor #226 (middle row) shows intermediate nuclear and cytoplasmic Jab1 expression associated with moderate EGFR and absence of S100A7 expression. Tumor #230 (bottom row) shows low nuclear but high cytoplasmic Jab1 expression associated with the absence of EGFR or S100A7 expression. EGFR, epidermal growth factor receptor; Jab1, c-Jun activation domain-binding protein-1.

Mentions: To further explore the relationship between EGFR and Jab1 expression in vivo, we examined the expression of these genes in a series of 424 invasive breast tumors using TMAs. The characteristics of the cohort are outlined in Table 1. The relationship between nuclear expression of Jab1 and the level of EGFR was assessed, together with the level of S100A7, because of the previously established strong relationship between S100A7 expression and Jab1. In analysis of the entire tumor cohort, high levels of Jab1, EGFR, and S100A7 were seen in 154/424 (36%), 42/424 (10%), 144/424 (34%) cases, respectively (Figure 5). Jab1 was not associated with prognostic factors or biomarkers, including grade, axillary nodal status, tumor size, ER, PR, EGFR, or S100A7, or with overall patient survival when examined in the entire cohort. In subgroup analysis of the ERα+ subgroup, no significant associations were observed. However, in subgroup analysis of the ERα- subgroup (n = 154), Jab1 levels were associated with axillary node-positive status (P = 0.019, t test) and higher levels of Jab1 nuclear expression were associated with both EGFR (P = 0.019, t test) and S100A7 (P = 0.036, t test) (Table 2). Notably, higher Jab1 levels were more strongly associated with combined EGFR+/S100A7+ versus EGFR-/S100A7- status within this subgroup (P = 0.004, t test).


Jab1 is a target of EGFR signaling in ERalpha-negative breast cancer.

Wang J, Barnes RO, West NR, Olson M, Chu JE, Watson PH - Breast Cancer Res. (2008)

Jab1 nuclear expression correlates with increased EGFR and S100A7 in breast tumors. EGFR, S100A7, and Jab1 were detected by immunohistochemistry in breast tumors represented within a tissue microarray. Representative staining is shown for all three markers and in three separate tumors. Tumor #188 (top row) shows high nuclear Jab1 expression associated with high EGFR and S100A7 expression. Tumor #226 (middle row) shows intermediate nuclear and cytoplasmic Jab1 expression associated with moderate EGFR and absence of S100A7 expression. Tumor #230 (bottom row) shows low nuclear but high cytoplasmic Jab1 expression associated with the absence of EGFR or S100A7 expression. EGFR, epidermal growth factor receptor; Jab1, c-Jun activation domain-binding protein-1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481501&req=5

Figure 5: Jab1 nuclear expression correlates with increased EGFR and S100A7 in breast tumors. EGFR, S100A7, and Jab1 were detected by immunohistochemistry in breast tumors represented within a tissue microarray. Representative staining is shown for all three markers and in three separate tumors. Tumor #188 (top row) shows high nuclear Jab1 expression associated with high EGFR and S100A7 expression. Tumor #226 (middle row) shows intermediate nuclear and cytoplasmic Jab1 expression associated with moderate EGFR and absence of S100A7 expression. Tumor #230 (bottom row) shows low nuclear but high cytoplasmic Jab1 expression associated with the absence of EGFR or S100A7 expression. EGFR, epidermal growth factor receptor; Jab1, c-Jun activation domain-binding protein-1.
Mentions: To further explore the relationship between EGFR and Jab1 expression in vivo, we examined the expression of these genes in a series of 424 invasive breast tumors using TMAs. The characteristics of the cohort are outlined in Table 1. The relationship between nuclear expression of Jab1 and the level of EGFR was assessed, together with the level of S100A7, because of the previously established strong relationship between S100A7 expression and Jab1. In analysis of the entire tumor cohort, high levels of Jab1, EGFR, and S100A7 were seen in 154/424 (36%), 42/424 (10%), 144/424 (34%) cases, respectively (Figure 5). Jab1 was not associated with prognostic factors or biomarkers, including grade, axillary nodal status, tumor size, ER, PR, EGFR, or S100A7, or with overall patient survival when examined in the entire cohort. In subgroup analysis of the ERα+ subgroup, no significant associations were observed. However, in subgroup analysis of the ERα- subgroup (n = 154), Jab1 levels were associated with axillary node-positive status (P = 0.019, t test) and higher levels of Jab1 nuclear expression were associated with both EGFR (P = 0.019, t test) and S100A7 (P = 0.036, t test) (Table 2). Notably, higher Jab1 levels were more strongly associated with combined EGFR+/S100A7+ versus EGFR-/S100A7- status within this subgroup (P = 0.004, t test).

Bottom Line: EGF treatment of cell lines resulted in increased Jab1 nuclear expression.This effect was inhibited by the ERK pathway inhibitor, PD98059.EGF treatment was also associated with colocalization of pERK (phosphorylated ERK) and Jab1 as well as regulation of the Jab1 downstream target gene, p27.

View Article: PubMed Central - HTML - PubMed

Affiliation: Deeley Research Center, BC Cancer Agency, Vancouver Island Center, Victoria, BC, Canada.

ABSTRACT

Introduction: c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional signaling protein that previously has been shown to be a master regulator of a poor prognostic gene signature in invasive breast cancer and to mediate the action of S100A7. Since epidermal growth factor receptor (EGFR), like S100A7, is often expressed in estrogen receptor-alpha-negative (ERalpha-) breast cancer, we set out to investigate the role of Jab1 in mediating EGFR signaling, another facet of the ERalpha- phenotype.

Methods: MDA-MB-231 and MDA-MB-468 ERalpha-/EGFR+ cell lines were assessed for localization of Jab1 and levels of downstream genes by immunofluorescence and nuclear protein extract assay following treatment with epidermal growth factor (EGF) and extracellular signal-regulated kinase (ERK) pathway inhibitor. A cohort of 424 human breast tumors was also assessed by immunohistochemistry.

Results: EGF treatment of cell lines resulted in increased Jab1 nuclear expression. This effect was inhibited by the ERK pathway inhibitor, PD98059. EGF treatment was also associated with colocalization of pERK (phosphorylated ERK) and Jab1 as well as regulation of the Jab1 downstream target gene, p27. When Jab1 activity was knocked down, p27 levels were restored to pre-EGF treatment level. Analysis of EGFR and Jab1 expression in a cohort of invasive breast tumors by tissue microarray and immunohistochemistry confirmed a relationship between EGFR and increased nuclear Jab1 within the ERalpha- subset (n = 154, P = 0.019). The same association was also confirmed for S100A7 and Jab1 (P = 0.036), and high Jab1 nuclear expression was most frequent in tumors that were positive for both EGFR and S100A7 (P = 0.004).

Conclusion: Jab1 is a target of EGFR signaling in ERalpha- cell lines and breast tumors and therefore may be a common central factor and potential therapeutic target for important cell signaling pathways in ERalpha- breast cancer.

Show MeSH
Related in: MedlinePlus